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WO 2010/127399 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 11 November 2010 (11.11.2010) WO 2010/127399 Al (51) International Patent Classification: (74) Agent: MONGER, Carmela; Walter and Eliza Hall In C12Q 1/68 (2006.01) GOlN 35/00 (2006.01) stitute of Medical Research, IG Royal Parade, Parkville, GOlN 33/48 (2006.01 ) Melbourne, Victoria 3052 (AU). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/AU20 10/000524 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) Date: International Filing CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 6 May 2010 (06.05.2010) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 2009901989 6 May 2009 (06.05.2009) AU SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant (for all designated States except US): WAL¬ TER AND ELIZA HALL INSTITUTE OF MEDICAL (84) Designated States (unless otherwise indicated, for every RESEARCH [AU/AU]; IG Royal Parade, Parkville, kind of regional protection available): ARIPO (BW, GH, Melbourne, Victoria 3052 (AU). GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (72) Inventors; and TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (75) Inventors/Applicants (for US only): LINDEMAN, Ge¬ EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, offrey [AU/AU]; WEHI, IG Royal Parade, Parkville, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, Melbourne, Victoria 3052 (AU). SMYTH, Gordon [AU/ SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, AU]; IG Royal Parade, Parkville, Melbourne, Victoria GW, ML, MR, NE, SN, TD, TG). 3052 (AU). VISVADER, Jane [AU/AU]; IG Royal Pa Published: rade, Parkville, Melbourne, Victoria 3052 (AU). WU, Di [AU/AU]; IG Royal Parade, Parkville, Melbourne, Victo — with international search report (Art. 21(3)) ria 3052 (AU). — with sequence listing part of description (Rule 5.2(a)) (54) Title: GENE EXPRESSION PROFILES AND USES THEREOF (57) Abstract: A method for stratifying cancer in a subject comprising determining gene-set expression in a sample from a sub ject. The set is preselected from genes which are: (a) selectively or differentially expressed in CD49FEpCAM + luminal epithelial progenitor cells compared to basal epithelial (MaSC enriched) or mature luminal epithelial cells; and/or (b) selectively or differen tially expressed in CD491*Ε pCAM basal epithelial progenitor cells compared to luminal progenitor and mature luminal epithelial cells; and/or (c) selectively or differentially expressed in CD49f EpCAM + mature luminal epithelial cells compared to basal epithe lial and luminal progenitor epithelial cells; and/or (d) selectively or differentially expressed in CD49f EpCAM stromal fibroblasts cells compared to basal epithelial and luminal epithelial cells. A method for diagnosis, prognosis or treatment of basal-like breast cancer and/or a BRCAl -deficiency associated form of cancer comprising (i) determining expression of a set of genes in a sample where the gene set is preselected to comprise genes which are selectively or differentially expressed in CD49f pCAM + epithelial luminal progenitor cells compared to their expression by control cells such as at least basal epithelial cells or mature luminal ep ithelial cells. Gene sets are provided in Tables 10 to 17. Preferred gene sets include KIT. Methods of treatment or prevention in clude administering agents that modulate the activity of gene set expression products, such as KIT polypeptide. Diagnostic probes and kits are included. Methods of reducing proliferation of normal or pre-neoplastic or neoplastic luminal progenitor cells in hu man mammary epithelium are provided including administering an agent that down modulates KIT activity. GENE EXPRESSION PROFILES AND USES THEREFOR FIELD The specification describes cell-specific molecular markers, targets and methods useful for the stratification and treatment of cancers including breast cancers. BACKGROUND Bibliographic details of references in the subject specification are also listed at the end of the specification. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates. Gene and protein profiling technologies now use sophisticated algorithms to allow simultaneous characterization of multiple genes or proteins in an individual. This information, when linked to accurate prognostic algorithms promises to enhance our ability to optimise treatment options. Furthermore, information concerning changes in the expression of single or multiple genes over time within a single cell type or between cell types, when correctly interpreted, promises to provide new targets for therapeutic intervention and new diagnostic options. However, the problem still exists of selecting relevant targets and accurate markers. One field where this problem is particularly acute is the field of cancer where transformed cells of uncertain origin exist along side normal and pre-neoplastic cells of various lineages. Breast cancer remains a leading cause of death fof women. Human breast tissue is organised, at least in part, as a branching network of ducts and lobules comprising two types of mature epithelial cell and their precursors. Luminal epithelial cells form th e milk producing secretory cells of the lobules which are surrounded by an outer layer of contractile basal (myoepithelial) cells. The art recognises several different cell types within the breast including luminal and basal (myoepithelial) progenitors, bipotent progenitors, stem cells and stromal cells. The different cells may be categorised by a range of morphological, genetic or proteinaceous markers. Although a number of genes and proteins associated with breast cancer have been identified, reliable prognostic tools and therapeutic treatments are highly sought after. One clinically useful example of genes associated with breast, ovarian, prostate, pancreatic, colon and various other forms of cancer are the BRCAl and BRC A2 genes. Here, certain mutations in BRCAl or BRCA2 are linked to a substantial proportion of familial forms of breast cancer, which account for approximately 5-10% of breast cancers. Reduced expression of BRCAl and BRCA2 genes are also found in sporadic (non-familial) forms of cancers. In relation to proteinaceous markers, breast tumor samples may be tested for oestrogen receptor expression and, if positive, subjects may be treated with oestrogen antagonists. In another example, breast tumor samples may be tested for human epidermal growth factor receptor 2 (ErbB2) expression and positive subjects may be treated with ErbB2 antagonists. Breast cancer appears to be essentially a group of diseases that display widely different clinical course and response to treatment. Various different and fairly imprecise breast cancer categories are described according to mainly morphologic, genetic (including surface marker, gene or protein profile), immunophenotypic and clinical features. The relationship between normal and pre-neoplastic breast cells and these tumor subtypes is poorly understood and this confounds the process of identifying markers and targets and determining effective intervention strategies. The difficulty of accurately subtyping breast cancer leads to inaccurate prognosis and much uncertainty for medical practitioners and their patients. Gene expression profiling information derived using DNA microarrays to analyse expression from multiple thousands of genes has led to the subdivision of breast cancer into at least five different subtypes based upon patterns of expression segregating into different clusters (See, for example, Sorlie et al, Proc. Nat. Acad. Sci, USA 98 (19): 10869-10874, 2001; Neilsen et al, Clinical Cancer Research 70:5367-5374, 2004; Herschkowitz et al, Genome Biol. 8 R76, 2007, Hu et al, BMC Genomics 7: 96, 2006). One subtype is the most aggressive (carries the poorest prognosis) "basal-like" tumor type thought to arise from basal epithelial cells and to have a gene expression profile similar to normal breast basal (myoepithelial or mammary stem cell (MaSC)) cells. The breast tumor subtypes, "Luminal A", "Luminal B", "Her2+/ER-", "basal-like" and "normal breast like" subtypes are recognised by Hu et al. {supra). Herschkowitz et al, 2007 {supra) further describe a "claudin-low" subgroup that is oestrogen receptor negative, progesterone receptor negative and human epidermal growth factor (HER2/neu) overexpression negative (referred to as "triple negative") and expresses Claudin 3 and E-cadherin. The "basal-like" breast cancer subtype has also been characterised as "triple negative". In addition, "basal-like" breast tumor cells are typically epidermal growth factor receptor
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