Background:?Postpartum?breast?cancers,?defined?as?breast?cancers?diagnosed?within?5-?10?years?of?last? childbirth,?are?more?than?twice?as?likely?to?become?metastatic?and?result?in?death.?This?devastating?diagnosis? affects?thousands?of?young?women?annually.?Our?previous?research?revealed?that?non-?invasive?breast?tumor? cells?become?invasive?and?metastatic?in?postpartum?mice?compared?to?controls?in?nulliparous?mice.?We?also? revealed?a?novel?feedback?loop?involving?collagen?mediated?upregulation?of?COX-?2,?which?mediates?invasion? and?metastasis?in?postpartum?mice.?Subsequent?gene?expression?analysis?revealed?a?significant?and?specific? upregulation?of?SEMA7A?mRNA?in?postpartum?breast?tumor?cells.?The?SEMA7A?gene?encodes?for?semaphorin? 7a?(Sema7a),?a?signaling?molecule?that?drives?neural?development,?immunity,?and?tissue?remodeling?in?the? lung.?Our?preliminary?data?demonstrate?that?silencing?of?SEMA7A?cell?line?derived?postpartum?breast?cancer? xenografts?delays?growth,?progression?to?invasive?cancer,?and?reduces?lymphangiogenesis?in?the?tumor? microenvironment.?In?addition,?we?have?analyzed?our?young?women?s?breast?cancer?cohort?to?reveal?that? SEMA7A?protein?is?significantly?increased?in?postpartum?patient?tumors?and?in?nulliparous?patient?tumors?that? subsequently?recurred.?Thus,?we?postulate?that?SEMA7A?is?also?a?general?mediator?of?breast?tumor? progression.?In?support?of?this,?our?gene?expression?analysis?of?multiple?human?breast?cancer?datasets?reveals? that?SEMA7A?mRNA?expression?is?associated?with?early?recurrence,?metastasis,?and?death.?Cumulatively,? these?data?support?the?hypothesis?that?SEMA7A?promotes?tumor?progression?in?breast?cancer?patients?and? may?be?an?important?therapeutic?target.?Objective/Hypothesis:?A?collagen-?mediated?COX-?2/SEMA7A? signaling?axis?is?key?for?invasion,?stromal?remodeling,?and?induction?of?vascular?remodeling?in?the? tumor?microenvironment,?all?of?which?ultimately?drive?metastasis.?Specific?Aims:?(1)?Determine?how? collagen?leads?to?upregulation?of?COX-?2?and?SEMA7A?and?whether?targeting?COX-?2?in?combination?with? silencing?of?SEMA7A?will?block?tumor?cell?invasion.?(2)?Define?the?mechanisms?by?which?SEMA7A?promotes? vascular?remodeling?and?metastasis,?determine?whether?targeting?or?co-?targeting?of?SEMA7A?and?COX-?2?will? block?metastasis,?and?define?the?relationship?between?SEMA7A?and?COX-?2?in?postpartum?breast?tumors.?? Cancer?relevance:?To?establish?clinical?relevance,?we?will?examine?the?relationship?between?SEMA7A?and? COX-?2?protein?expression,?along?with?collagen?and?the?vasculature,?using?multi-?color?immunostaining?and? correlate?with?invasion?and?recurrence?in?our?postpartum?breast?cancer?patient?tissues.?The?expected? outcomes?are?identification?of?mechanisms?by?which?COX-?2?and?SEMA7A?support?breast?tumor?progression.? Such?results?could?positively?impact?thousands?of?breast?cancer?patients?by?defining?new?therapies?targeted?at? the?SEMA7A?pathway.?Given?that?SEMA7A?expression?is?generally?low?in?adult?tissues?direct?targeting?of? SEMA7A?could?have?low?toxicity.???

R01CA211696

2017-06-19

2022-05-31